Monocyte-derived macrophages are plastic immune cells, whose phenotype adjust to the necessities of the organism. Inflammation drive monocyte differentiation into macrophages, then macrophages acquire different activation states, as the inflammatory process continues. The TGF-β-induced M2c macrophages are efficient phagocytes necessary for the resolution of inflammation, by clearance of apoptotic cells (efferocytosis) and cellular debris. Failure in the mechanisms that drive the resolution of inflammation lead to diseases such as atherosclerosis. Soluble epoxide hydrolase (sEH) is an enzyme whose inhibition has shown decreased inflammation and athero-protective effects. Currently is unknown whether these effects are mediated by macrophages, therefore we aim to investigate the effect of sEH on macrophage polarization through a TGF-β dependent mechanism.

Our data shown that sEH was expressed across all macrophage polarization states, with overexpressed sEH levels after M2c repolarization with TGF-β1. Modulation of the TGF-β receptor I (ALK5) by using a pharmacological inhibitor, results in the downregulation of sEH. Indeed, the loss of the endogenous ALK5 antagonist, SMOC1, increased sEH expression at protein and mRNA level. Furthermore, SMOC1 downregulation induced a marked increase in phagocytosis of zymosan particles M2c macrophages, and this effect is rescued by the addition of recombinant SMOC1 prior to M2c polarization.

In conclusion, TGF-β induce sEH expression via an ALK5 dependent mechanism, and inhibition of this pathway leads to an abnormal phagocytic phenotype. Future studies are going to focus on resolution of inflammation in atherosclerosis pathology by making use of a special mouse model that lacks sEH specifically in their myeloid cells.